The ultimate goal of the proposed research is to determine whether some age-dependent alterations occur in the properties of a pivotal metabolic autoregulatory system in brain tissue. Such changes could be involved in the progressively declining tolerance for metabolic stress and the loss of neuronal elements which characterize the aging process in the brain. The local autoregulator is the purine nucleoside adenosine--an agent which has been found to modulate neurotransmitter release, to stimulate adenylate cyclase activity, to be released from brain tissue during hypoxia, and to regulate perfusion pressure in cerebral vessels. The characteristics of the sites through which adenosine produces these effects will be examined in mature and aged animals in an effort to determine whether there is some loss of cellular responsiveness to adenosine with age. Cerebral cortical and striatal synaptosomes from mature and aged animals will be evaluated for their ability to take up norepinephrine and dopamine respectively and to release these neurotransmitters in response to depolarization. The effectiveness of adenosine in modulating the release of these transmitters will be compared in the tissues from the two groups of animals. Adenosine receptor function in the mature and aged animals will be determined through an examination of the receptor-coupled adenylate-cyclase activity in cell-free preparations from the cortex and striatum. Finally, the capacity of brain tissue to synthesize and release adenosine in response to hypoxia will be compared in the two groups. The important metabolic regulatory functions of adenosine in the brain strongly suggest that any compromise in the performance of this system could have very serious consequences for brain cells which are so dependent on a constant supply of metabolic substrates.